This application is a competitive renewal application (5 RO1 MH54192-07). The dopamine (DA) hypothesis of schizophrenia proposes that positive symptoms of the illness are associated with hyperactivity of DA transmission. Recently, several groups have demonstrated that binding competition between endogenous DA and D2 receptor ligands enables measurement of changes in DA concentration in the vicinity of D2 receptors with PET and SPECT. During the first cycle of this grant, we used this approach to study amphetamine-induced DA release with SPECT and [123I]IBZM in schizophrenia. We observed that this response was elevated in schizophrenia. During the second cycle of this grant, we studied baseline occupancy of D2 receptors in schizophrenia, again using SPECT and [123I]IBZM. We observed that this occupancy was elevated in schizophrenia and that elevated DA transmission was predictive of a good treatment response to antipsychotic medication. An important limitation of the work carried out so far is that, due to the limited spatial resolution of SPECT, DA transmission could be studied only at the level of the striatum as a whole. Using [llC]raclopride and high resolution PET, we recently demonstrated the reliability of measuring DA transmission within the limbic, associative and sensorimotor subdivisions of the striatum. Because of the apparent "mesolimbic" selectivity of new antipsychotic drugs, it is widely accepted that dysfunction of DA transmission in schizophrenia involves mesolimbic rather than nigrostriatal DA pathways. In preliminary data obtained with high resolution PET and [11C]raclopride, we made the surprising observation that DA transmission in schizophrenia is not elevated in the ventral striatum, as anticipated, but in the precommissural dorsal caudate nucleus (preDCA), and that elevated preDCA DA transmission is related to antipsychotic efficacy. Given the low number (n = 8) of subjects with schizophrenia included in these preliminary data, this finding, which challenges common views about DA in schizophrenia, should be viewed with caution. Therefore, in the third cycle of this grant, we propose to study alterations of DA transmission in striatal subregions with PET and [11C]raclopride in 36 patients with schizophrenia and 36 controls. Given that the preDCA is the striatal subregion that modulates information processing in the dorsolateral prefrontal cortex (DLPFC), altered DA transmission in the preDCA might be involved in the DLPFC dysfunction observed in schizophrenia. This finding, if confirmed, might contribute to a better understanding of the pathophysiology of this illness.